Maternal exercise and high-fat diet affect hypothalamic neural projections in rat offspring in a sex-specific manner.

This study aimed to investigate the effect of maternal high-fat (HF) diet and exercise during gestation and lactation on hypothalamic neural projection development in the offspring. Pregnant Sprague-Dawley rats were fed a CHOW or HF diet during gestation and lactation, and further divided into two subgroups: voluntary exercised and sedentary. Offspring's brains and tissue were collected at weaning and 16 weeks of age. Maternal exercise downregulated dams' body weight and food intake during lactation, but failed to normalize increased fat weight, plasma and milk leptin levels of HF dams at weaning. Maternal HF diet significantly increased offspring's body weight, adipose depots, plasma insulin, and leptin at weaning and had long-term effect on body weight of male offspring, while maternal exercise decreased offspring's body weight from 3 to 5 weeks of age in both sexes. At weaning, maternal exercise decreased αMSH fiber density and maternal HF diet impaired agouti-related peptide fiber density in the paraventricular nucleus of hypothalamus of male pups, while maternal HF diet disrupted αMSH fiber density in the paraventricular nucleus of hypothalamus of female pups. The impaired αMSH fiber density was consistent with reduced STAT3 signaling in the arcuate nucleus of hypothalamus, while the reduced agouti-related peptide fiber density was consistent with reduced ERK1/2 signaling in the arcuate nucleus of hypothalamus. The impaired hypothalamic projections were compensated in adulthood in both sexes. Our findings suggest that maternal HF diet and exercise exerts different effects on hypothalamic neural projections development through distinct signaling pathways in a sex-specific manner.

Maternal exercise during gestation and lactation decreases high-fat diet preference by altering central reward system gene expression in adult female offspring from high-fat fed dams.

Exposure to maternal high-fat (HF) diet during gestation and lactation alters adult offspring's feeding behavior and diet preference. However, the impact of maternal exercise on offspring's diet preference and reward system development is less studied. In this study, we investigate the effect of perinatal maternal exercise on the development of diet preference, dopamine- and opioid-related gene expression in the central reward system in female offspring from HF-fed Sprague-Dawley rat dams. We found maternal HF diet did not alter adult offspring HF preference, but influenced offspring's dopamine and opioid system both at weaning and in adulthood, and these offspring retained higher body weight in adulthood. However, offspring from dams exposed to both HF diet and exercise during gestation and lactation had normalized body weight, decreased fat mass and lower HF-diet preference but increased energy intake in adulthood. The dopamine- and opioid-related gene expression in central reward system and POMC expression in hypothalamus was elevated in these adult offspring. We conclude that maternal exercise during gestation and lactation can potentially overcome the negative effects of perinatal exposure to HF diet in female offspring by altering their diet preference, central reward system signaling and hypothalamus neuropeptide expression.

Prenatal exercise reverses high-fat-diet-induced placental alterations and alters male fetal hypothalamus during late gestation in rats†.

Maternal high-fat (HF) diet negatively affects maternal metabolism and placental function. This study aimed to determine whether gestational exercise prevents the effect of HF diet on placental amino acid transporter expression and nutrient-sensing signaling and the fetal response. Pregnant Sprague-Dawley rats were either fed with a CHOW (13.5% fat) or HF (60% fat) diet during gestation and further divided into two subgroups: voluntary exercised and sedentary. Placentae were collected on gestational day (GD) 14 and GD20, and male placentae were used in this study. We found that gestational exercise ameliorated the detrimental effects of HF diet on dams' adiposity, plasma leptin, and insulin concentrations. Maternal exercise did not influence fetoplacental growth but affected male fetal hypothalamic Leprb, Stat3, Insr, Agrp, and Pomc expressions on GD20. Maternal HF diet decreased placental labyrinth thickness and increased system A amino acid transporter SNAT2 expression, while these changes were normalized by exercise. The activation of placental mechanistic target of rapamycin complex 1/4E-BP1 and LepRb/STAT3 signaling might contribute to the increased placental SNAT2 expression in HF-fed dams, which were reversed by exercise on GD20. These data highlight that gestational exercise reverses HF-diet-induced placental alterations during late gestation without influencing fetal growth. However, maternal exercise altered fetal hypothalamic gene expression, which may affect long-term offspring health.

Effects of saccharin supplementation on body weight, sweet receptor mRNA expression and appetite signals regulation in post-weanling rats.

Non-nutritive sweeteners have been considered to promote diet healthfulness by delivering a pleasant sweet taste without calories. We investigated the effects of long term supplementation with drinks containing saccharin on body weight and possible mechanisms of the effects in post-weanling rats. Our results showed that saccharin solution intake increased food intake and energy intake in male rats. In males, saccharin solution intake increased TIR3 mRNA expression in the taste buds and ghrelin receptor mRNA expression both in the taste buds and hypothalamus, whereas no effects were observed in females. These results suggest the effects of saccharin solution exposure on food intake and body weight gain may be different in developmental males and females. In males, peripheral sweet taste receptors and both peripheral and central ghrelin receptors may be involved in the effect of saccharin solution intake to promote food intake and weight gain.

Ire1α in Pomc Neurons Is Required for Thermogenesis and Glycemia.

Whether neuronal inositol-requiring enzyme 1 (Ire1) is required for the proper regulation of energy balance and glucose homeostasis is unclear. We found that pro-opiomelanocortin (Pomc)-specific deficiency of Ire1α accelerated diet-induced obesity concomitant with a decrease in energy expenditure. This hypometabolic phenotype included deficits in thermogenic responses to diet and cold exposure as well as "beiging" of white adipose tissue. We also demonstrate that loss of Ire1α in Pomc neurons impaired whole-body glucose and insulin tolerance as well as hepatic insulin sensitivity. At the cellular level, deletion of Ire1α in Pomc neurons elevated hypothalamic endoplasmic reticulum (ER) stress and predisposed Pomc neurons to leptin and insulin resistance. Together, the current studies extend and confirm conclusions that Ire1α-Xbp1s and associated molecular targets link ER stress in arcuate Pomc neurons to aspects of normal energy and glucose homeostasis.

Large litter rearing improves leptin sensitivity and hypothalamic appetite markers in offspring of rat dams fed high-fat diet during pregnancy and lactation.

Maternal high-fat (HF) diet has long-term consequences on the offspring's metabolic phenotype. Here, we determined the effects of large litter (LL) rearing in offspring of rat dams fed HF diet during gestation and lactation. Pregnant Sprague-Dawley rats were maintained on standard chow (CHOW) or HF diet throughout gestation and lactation. Pups were raised in normal litters (NLs) (10 pups/dam) or LLs (16 pups/dam) during lactation, resulting in 4 groups: CHOW-NL, CHOW-LL, HF-NL, and HF-LL. The offspring were weaned onto to either CHOW or HF diet on postnatal day 21. Male and female pups with maternal HF diet (HF-NL) had greater body weight and adiposity, higher plasma leptin levels, impaired glucose tolerance, abnormal hypothalamic leptin signaling pathways (lower leptin receptor-b [OB-Rb] and signal transducer and activator of transcription 3, higher suppressor of cytokine signaling 3 mRNA expression) and appetite markers (lower neuropeptide Y and Agouti-related peptide mRNA expression), and reduced phospho-signal transducer and activator of transcription 3 level in response to leptin in the arcuate nucleus at weaning, whereas LL rearing normalized these differences. When weaned onto CHOW diet, adult male offspring from HF diet-fed dams continued to have greater adiposity, higher leptin levels, and lower hypothalamic OB-Rb, and LL rearing improved them. When weaned onto HF diet, both adult male and female offspring with maternal HF diet had greater body weight and adiposity, higher leptin levels, impaired glucose tolerance, lower OB-Rb, and higher suppressor of cytokine signaling 3 in hypothalamus compared with those of CHOW dams, whereas LL rearing improved most of them except male OB-Rb expression. Our data suggest that LL rearing improves hypothalamic leptin signaling pathways and appetite markers in an age- and sex-specific manner in this model.

Involvement of brain ANG II in acute sodium depletion induced salty taste changes.

Many investigations have been devoted to determining the role of angiotensin II (ANG II) and aldosterone (ALD) in sodium-depletion-induced sodium appetite, but few were focused on the mechanisms mediating the salty taste changes accompanied with sodium depletion. To further elucidate the mechanism of renin-angiotensin-aldosterone system (RAAS) action in mediating sodium intake behavior and accompanied salty taste changes, the present study examined the salty taste function changes accompanied with sodium depletion induced by furosemide (Furo) combined with different doses of angiotensin converting enzyme (ACE) inhibitor, captopril (Cap). Both the peripheral and central RAAS activity and the nuclei Fos immunoreactivity (Fos-ir) expression in the forebrain area were investigated. Results showed that sodium depletion induced by Furo+low-Cap increased taste preference for hypertonic NaCl solution with amplified brain action of ANG II but without peripheral action, while Furosemide combined with a high dose of captopril can partially inhibit the formation of brain ANG II, with parallel decreased effects on salty taste changes. And the resulting elevating forebrain ANG II may activate a variety of brain areas including SFO, PVN, SON and OVLT in sodium depleted rats injected with Furo+low-Cap, which underlines salty taste function and sodium intake behavioral changes. Neurons in SFO and OVLT may be activated mainly by brain ANG II, while PVN and SON activation may not be completely ANG II dependent. These findings suggested that forebrain derived ANG II may play a critical role in the salty taste function changes accompanied with acute sodium depletion.

Intragastric administration of evodiamine suppresses NPY and AgRP gene expression in the hypothalamus and decreases food intake in rats.

Evodiamine (Evo), an alkaloidal component extracted from the fruit of Evodiae fructus (Evodia rutaecarpa Bentham, Rutaceae), decreases the body weight of rats through a poorly defined mechanism. The hypothalamus is one of the areas in the brain linked to the control of food intake and energy expenditure. We postulate that Evo mediates this activity by modulating feeding-related peptides in the hypothalamus. We investigated the effects of Evo on food intake, body weight, the mRNA expression and peptide level of feeding-related peptides in the hypothalamus, in male rats. The juvenile rats of 5 weeks old were used at the start of the experiment. Evo (40 mg/kg or 4 mg/kg) was administered intragastrically for 25 days, and food intake and body weight of rats were recorded daily. Blood samples were collected for leptin radioimmunoassay (RIA). Real-Time PCR was used to analyze the mRNA expression. Western Blotting and immunohistochemistry were used to analyze the peptide. Our results show that intragastric administration of Evo (40 mg/kg) decreased rate of food intake and body weight increase following rat growth, reduced orexigenic neuropeptide Y (NPY) and agouti-gene related protein (AgRP) mRNA levels and NPY peptide level in the arcuate nucleus (ARC) of the hypothalamus, but it increases the circulating level of leptin. Intragastric administration of a smaller dose of Evo (4 mg/kg) was ineffective. These data suggest that Evo decreases food intake, and therefore body weight, partly by down-regulating NPY and AgRP mRNA expression and peptide expression in the ARC of the hypothalamus.

Role of the lateral hypothalamus in modulating responses of parabrachial gustatory neurons in the rat.

The lateral hypothalamus (LH) receives projections from the parabrachial nucleus (PBN) gustatory neurons and sends efferent projections to the PBN. To examine if the LH is involved in modulating activity of gustatory neurons in the PBN, we examined the effects of electrical stimulation and electrolytic lesions of the LH on the response of PBN gustatory neurons, using extracellular recording techniques. Among 45 PBN taste neurons recorded, 60% were affected by LH stimulation and 73% were affected by LH lesions. During LH stimulation, the responses of most affected PBN neurons were inhibited with the magnitude significantly lower than that obtained before stimulation (P<0.05). In contrast, LH lesions facilitated the response. Based on the best-stimulus category, the responses of the NaCl-best neurons to NaCl and HCl and the QHCl-best neurons to HCl and QHCl were significantly suppressed during LH stimulation (P<0.05). After lesions of the LH, however, the response to HCl in NaCl-best PBN neurons was significantly increased (P<0.05). Analysis of across-unit patterns indicated that LH stimulation decreased the correlations between NaCl and other stimuli, and increased those between QHCl and other stimuli. After LH lesions, the correlations between NaCl and other tastants were higher than those before lesions. These findings suggest that the LH mediates feeding and taste via modulating the activity and chemical selectivity of PBN gustatory neurons.